Production of steroids



United States Patent PRODUCTION OF STEROIDS Robert B. Woodward, Belmont, Mass., assignor to Research Corporation, New York, N. 'Y., a corporation of New York No Drawing. Application May 19, 1953, Serial No. 356,085

3 Claims. (Cl. 260-3405) (xvb) into the D-homosteroid (XVII) and to the product thereby obtained.

It has been found that by converting the carboxyethyl compound (XVb) into the lactone (XVI) on o XVI and cyclizing the latter compound into the D-homosteroid (XVII) by reaction with a methyl Grignard reagent and treating the reaction product wtih a base, the lactone from the Cit-15011161 (XVb) CH I A p 0 011a H00 (XVb) which is very difiicult to separate completely from the 5- isomer, is not converted to a tetracyclic ketone if the reaction with the Grignard reagent is maintained at a temperature well below -35 C.

2,702,805 Patented Feb. 22, 1955 3-ket0 16,17 dihydroxy A 4 oxa D homoandrostadiene acetonide (XVI) enol lactone (XVI).

3-ket0-16,17 dihydroxy A D homoandrostadiene acetonide The crude enol lactone (ca. 13.5 g.) prepared as described in the foregoing is dissolved in a mixture of anhydrous benzene cc.) and anhydrous ether (200 cc.) and the solution cooled to -55 C. During 35 minutes, 310 cc. (300% excess) of a 0.48 N solution of methylmagnesium bromide in other is added to the well stirred mixture at -55 C.; a heavy precipitator forms at this point. The mixture is stirred at 45 C. to 55 C. for 4 hours, then poured into 0.5 N aqueous hydrochloric acid (500 cc.); the resulting mixture is shaken vigorously and then quickly separated. The extraction is repeated twice with chloroform, the extracts combined and washed with water; sodium hydroxide (l g.) is added and the solvents are removed in vacuo. The crude product (14.1 g. exclusive of the alkali) is dissolved in methanol (1000 cc.), sodium hydroxide (10.0 g.) in water cc.) is added and the solution refluxed in a nitrogen atmosphere for 2.5 hours. The methanol is then removed in vacuo and the residue thoroughly extracted with chloroform. The extracts are washed with water and evaporated in vacuo to yield 9.8 g. of crude product which is dissolved in benzene and passed over 100 g. of neutral alumina. The benzene and either eluates are combined and evaporated in vacuo to yield 4.45 g. of crystalline material which is recrystallized from methanol to yield 3.75 g. of 3-keto-16,17 dihydroxy A 'D homoandrostadiene acetonide XVII, M. P. 19820l C. (raised to ZOO-202 C. by recrystallization from methanol).

The method of the invention is eflective with other alkyl groups protecting the adjacent hydroxyl groups, including either two monovalent alkyls or a bivalent alkylene group.

This application is a continuation-in-part of my application Serial No. 220,977, filed April 13, 1951.

Methods of producing steroids from the compounds of the invention as described in my application Serial No. 356,086, filed May 19, 1953, now U. S. Patent No. 2,675,396.

I claim:

1. The method of cyclizing lactones of the general p C., treating the reaction product with a base and recovering the D-homosteroid of the formula thereby produced.

2. The method of producing the acetonide of 3-keto- 1 6 ,1 7-dihYdroxy A4361) D homoandrostadiene which comprises reacting a lactoneof the formula 0 0 with a methyl Grignard reagent at a temperature not ex- 'ce'eding 35 C., treating the reaction product with a base and separating the acetonide of 3-keto-16,17-dihydroxy-A -D-homoandrostadiene thereby produced.

7. v 4 3. The acetonide of 3-ket0-16,l7-dihydroxy-A -D- ho'moairdrostadieneof the'formul'a' 0/ \CHI No references cited. 

1. THE METHOD OF CYCLIZING LACTONES OF THE GENERAL FORMULA 